The present invention, in some embodiments thereof, relates to methods of diagnosing and treating motor neuron diseases and other cellular stress-related diseases.
Motor neuron diseases (MND) and frontotemporal dementia belong to a group of neurological disorders attributed to the destruction of motor neurons of the central nervous system and degenerative changes in the motor neuron pathway. Such diseases are different from other neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, olivopontocerebellar atrophy, etc., which are caused by the destruction of neurons other than motor neurons. Typically, MNDs are progressive, degenerative disorders that affect upper and lower motor neurons, leading to successive global muscular denervation. Generally, MNDs strike in middle age, although a wide age range of symptomatical disease onset can be observed, spanning from age 18 to 85 for several already studied mutants. Symptoms may include difficulty swallowing, limb weakness, slurred speech, impaired gait, facial weakness and muscle cramps. At the end stage of the disease, the respiratory musculature loses its innervation due to the death of motor neurons, which is usually the final cause of death of ALS patients. The cause(s) of most MNDs are not known, but environmental, toxic, viral or genetic factors are all suspects.
Motor neurons, including upper motor neurons and lower motor neurons, affect voluntary muscles, stimulating them to contract. Upper motor neurons originate in the cerebral cortex and send fibers through the brainstem and the spinal cord, and are involved in controlling lower motor neurons. Lower motor neurons are located in the brainstem and the spinal cord and send fibers out to muscles. Lower motor neuron diseases are diseases involving lower motor neuron degeneration. When a lower motor neuron degenerates, the muscle fibers it normally activates become disconnected and do not contract, causing muscle weakness and diminished reflexes. Loss of either type of neurons results in weakness, muscle atrophy (wasting) and painless weakness are the clinical hallmarks of MND (for further clinical definition see Online Mendelian Inheritance in Man®).
Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease characterized by a loss of pyramidal cells in the cerebral motor cortex (i.e., giant Betz cells), anterior spinal motor neurons and brain stem motor neurons, and degeneration thereof into pyramidal cells. ALS shows, from a clinical aspect, both upper motor neurons and lower motor neurons signs, and shows rapid clinical deterioration after onset of the disease, thus leading to death within a few years.
Like many other motor neuron diseases, only a small percentage (about 10%-20%) of ALS is inherited. Genetic epidemiology of ALS has revealed at least 12 chromosome locations accountable for the inheritance of disease (ALS1 to ALS12). Among these, several genes have been identified. The first was identified in 1993 as the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene that accounts for 20% of the autosomal dominant form of ALS [Rosen et al., (1993) Nature, 362(6415):59-62].
Frontotemporal Dementia is a neurodegenerative disease of humans which share in common with ALS etiopathological genetic causes, including mutations in genes such as TDP-43 and FUS. In addition a fraction of the patients' populations suffers from both Frontotemporal Dementia and ALS. Thus these diseases are on one molecular and clinical spectrum. Riluzole is the sole drug approved for ALS in U.S. and Japan.
Riluzole was originally developed as an anticonvulsant inhibiting glutamate release and has been reported in several clinical trials to exhibit only slight efficacy for the survival of ALS patients (Rowland L P and Shneider N A, 2001, N Engl J Med, 344, 1688-1700; and Turner M R and Parton M J, 2001, Semin Neurol 21: 167-175).
microRNAs (also known as miRNAs) are 20- to 24-nucleotide (nt) RNA molecule members of the family of non-coding small RNAs. microRNAs were identified in mammals, worms, fruit flies and plants and are believed to regulate the stability of their target messenger RNA (mRNA) transcripts in a tissue- and cell type-specific manner. Principally, micro-RNAs regulate RNA stability by either binding to the 3′-untranslated region (3′-UTR) of target mRNAs and thereby suppressing translation, or in similar manner to siRNAs, binding to and destroying target transcripts in a sequence-dependent manner.
microRNAs have been implicated in various neurological diseases such as ALS, Fragile X syndrome, spinal muscular atrophy (SMA), early onset parkinsonism (Waisman syndrome) and X-linked mental retardation (MRX3).
WO2010/06424 teaches the use of an agent which upregulates an activity or amount of miRNA-9 or miRNA-9* in the preparation of a medicament for the treatment of a motor neuron diseases (MNDs) including ALS.
U.S. Patent Application 20060247193 teaches administration of over 100 miRNAs for the treatment of MNDs including ALS.
U.S. Patent Application 20090246136 teaches administration of miR-206 and/or miR-1 for the treatment of MNDs including ALS.
Additional relevant background art includes U.S. Patent Application 20080176766.
Interestingly, specific mutations in genes encoding for RNA binding proteins, such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS)1,2 have been associated with the etiology of ALS3-6, as well as heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1; Kim et al. (2013) Nature 495(7442): 467-473) and valosin containing protein (VCP; Buchan et al. (2013) Cell 153(7): 1461-1474).
Buratti et al. 2010 (RNA Biology 7:4(420-429) describe a role of TDP-43 and FUS/TLS in RNA metabolism. Mislocalization of these proteins can alter the functioning of the Drosha processing enzyme both with regard to the general miRNA cellular population and for selected members.
Buratti et al. 2010 FEBS J. 2268-2281 shows that TDP-43 affect selected miRNA levels.
Kawahara et al. 2012 PNAS 109(9):3347-3352 shows that cytoplasmic TDP-43 interacts with the Dicer complex and promotes processing of a selected population of miRNAs via binding to the terminal loops.
Neuronal cytoplasmic protein aggregation and defective RNA metabolism were suggested to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders. Furthermore, polymorphic miRNA-mediated gene regulation has been specifically suggested as a mechanism for neurodegeneration, including motor neuron diseases7-10. In addition, it was recently demonstrated that loss of miRNAs bioprocessing by inactivation of Dicer1 is sufficient to cause spinal motoneuron degeneration11.